Inflammatory responses to implanted biomedical devices severely limit the biological performance of various devices in millions of patients. Furthermore, device-associated infections, such as catheter-associated bloodstream and surgical site infections result in substantial morbidity and mortality and contribute significantly to the high cost of caring for patients. The inability to directly image inflammatory responses and infections associated with implanted devices constitutes a major roadblock to the evaluation/diagnosis of device-associated inflammation and infection as well as the development of effective therapies. There is therefore a great need for the development of minimally invasive approaches to image inflammation and infection in vivo. The objective of this R21 exploratory research project is to establish fluorescent probes for in vivo imaging of device-associated inflammation and infection. Our central hypothesis is that probes that detect reactive oxygen species (ROS) associated with inflammatory responses will provide selective and sensitive imaging of device-associated inflammation and will be able to discriminate between aseptic inflammation and infection. Different ROS are produced by neutrophils and macrophages in response to implanted biomaterials and have been widely implicated to play a central role in the failure of medical implants. Furthermore, neutrophils and macrophages release ROS to kill bacteria and other infectious pathogens. We therefore postulate that ROS provide selective indicators of the severity and type of inflammation (aseptic vs. infection) within the vicinity of an implant. Our preliminary results demonstrating that hydrocyanine and peroxalate ROS sensors image inflammation in vivo support this hypothesis. Aim 1: To analyze ROS levels and specificity associated with device- associated inflammation and infection. Aim 2: To analyze the relationship among ROS/inflammation levels, bacterial growth and virulence in implant-related infection. The proposed research is highly innovative because it focuses on using ROS sensors to discriminate between aseptic and septic inflammation of an implanted device. This research will also generate longitudinal profiles correlating ROS signal/inflammation and bacterial growth and virulence. This research will have significant clinical impact as there are currently no fast, reliable and simple methods to evaluate the extent or outcome of device-related infections. PUBLIC HEALTH RELEVANCE: The inability to directly image inflammatory responses and infections associated with implanted devices constitutes a major roadblock to the evaluation/diagnosis of device performance as well as the development of effective therapies. We will establish fluorescent probes for in vivo imaging of device-associated inflammation and infection. This research will have significant clinical impact as there are currently no fast, reliable and simple methods to evaluate the extent or outcome of device-related infections.